Drug delivery systems are designed to provide a biocompatible reservoir of an active agent for the controlled release of the active agent dependent either on time, or on local conditions, such as pH. While macroscopic drug delivery systems such as transdermal patches, implantable osmotic pumps and implantable subcutaneous depots (e.g., NORPLANT™) have had some success, these technologies are often limited in, for example, achieving controlled dosing, compatibility with a variety of chemically distinct biomolecules, discomfort associated with administration and the like. Accordingly, there has been continuing interest in developing microscopic drug delivery systems aimed at overcoming some of the limitations inherent in the above described macroscopic systems.
In particular, there has been much recent research focused on developing novel microscopic drug delivery systems suitable for delivering therapeutic substances (e.g., drugs) in such a manner so as to get optimum benefits, including, for example, controlled release dosage forms, sustained release dosage forms, and the like. One such approach is using microencapsulation, e.g., microspheres or microcapsules, as carriers for drugs. Microencapsulation is a process whereby therapeutic substances, for example, small liquid droplets, are surrounded and enclosed by an intact shell. Microencapsulation is a particularly useful technology as it can be used to modify, delay and/or direct drug delivery and release following administration. A well-designed drug delivery system can overcome several of the problems of conventional therapy and enhance the therapeutic efficacy of a particular drug. It is the reliable means to deliver efficacious and effective dosages of drugs to appropriate target sites with specificity without untoward effects that has focused much attention to microencapsulation techniques as vital tools in drug delivery. These techniques obtain maximum therapeutic efficacy, as it becomes possible to deliver the agent to the target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects.
Microencapsulation provides a simple and cost-effective way to enclose bioactive materials, such as drugs, within a biocompatible coating or membrane for the purpose of protecting the bioactive materials and releasing the enclosed substances or their products in a controlled fashion. Microencapsulation techniques include, for example, natural and/or biodegradable polymers, polysaccharides, dendrimers, liposomes, micelles, optionally in functionalized forms, and other such biocompatible materials.
Microcapsules and microspheres are usually powders consisting of spherical particles 2 millimeters or less in diameter, usually 500 microns or less in diameter. If the particles are less than 1 micron, they are often referred to as nanocapsules or nano spheres. A description of methods of making and using microspheres and microcapsules can be found, for example in U.S. Pat. No. 5,407,609. Microcapsules and microspheres can be distinguished from each other by whether the active agent is formed into a central core surrounded by an encapsulating structure, such as a polymeric membrane, or whether the active agent is dispersed throughout the particle; that is, the internal structure is a matrix of the agent and excipient, usually a polymeric excipient. The release of the active agent from a microcapsule is often regulated by the biodegradation of the matrix material, usually a biodegradable polymeric material such as either poly(DL-lactide) (DL-PL) or poly(DL-lactide-co-glycolide) (DL-PLG) as the polymeric excipient.
Liposomes can be considered microcapsules in which the active agent core is encompassed by a lipid membrane instead of a polymeric membrane. Liposomes are artificial lipid vesicles consisting of lipid layers, where the active agent may be encapsulated inside the aqueous compartment of the liposome, or associated with the liposome on the surface via surface-coupling techniques. Liposomes can be prepared easily and inexpensively on a large scale and under conditions that are mild to entrapped active agents. They do not induce immune responses to themselves, and are used in humans for parenterally administered drugs.
While the high surface area/volume ratio of microcapsules, microspheres and liposomes favor the release of the active agent, their small size provides challenges in manufacturing. A wide variety of methods to prepare microcapsules and microspheres are described in the literature, e.g., U.S. Pat. No. 5,407,609. Several of these methods make use of emulsions to make microspheres, in particular to make microspheres less than 2 millimeters in diameter. To give a general example of such processes, one can dissolve a polymer in a suitable organic solvent (the polymer solvent), dissolve or disperse an agent in this polymer solution, disperse the resulting polymer/agent mixture into an aqueous phase (the processing medium) to obtain an oil-in-water emulsion with oil microdroplets dispersed in the processing medium, and remove the solvent from the microdroplets to form microspheres. These processes can also be performed with water-in-oil emulsions and with double emulsions. The use of emulsion-based processes that follow this basic approach is described in several U.S. patents, such as U.S. Pat. Nos. 3,737,337, 3,891,570, 4,384,975, 4,389,330, and 4,652,441.
As an alternative to traditional microencapsulation processes, yeast-based particles, or yeast microcapsules, can serve as readily available, biocompatible, biodegradable drug delivery particles. Yeast microcapsules are suitable for systemic drug delivery as well as oral, topical and inhalation mucosal drug delivery. Yeast microcapsules further have the ability to deliver therapeutic substances between cells to aid drug delivery.
The use of preformed natural microorganisms as microcapsules was first considered in the 1970s when it was observed that yeast cells (Saccharomyces cerevisiae), when treated with a plasmolyser, could be used to encapsulate water-soluble substances. When grown in fermenters, yeast microbial capsules reach a uniform size distribution and their physical makeup can be modified by simply altering the nutrient balance within the fermentation medium. In microencapsulation processes, the encapsulation can takes place in dead as well as live cells, indicating that encapsulation takes place by simple diffusion. Initial focus was on using yeast-based microencapsulation technology as a novel means of turning a volatile liquid into a powder for ease of handling. When it was observed that the yeast capsules released their payload on contact with the mucosal surfaces of the mouth more readily than in saliva alone, the possibility of targeted drug delivery using yeast cell capsules was first proposed.
Improved yeast microcapsule drug delivery systems are described for encapsulating and delivering a variety of soluble payload molecules including, but not limited to proteins, nucleic acids, antigens, small molecules, and the like. See, in particular U.S. Pat. No. 7,740,861, US 20050281781, US 20060083718, US 20080044438, US 20090209624, and US 20090226528. It is further desirable, however, to have the capability to encapsulate and deliver particulate payloads, such as, nanoparticles enabling a whole host of new functionalities in the field of drug delivery. In particular, nanoparticles have unusual properties that can be used to improve drug delivery, for example, facilitating cellular uptake, trafficking, regulating drug release, improving solubility, and the like.
The development of effective drug delivery systems presents multiple challenges, such as issues of drug solubility, targeting, in vivo stability and clearance, and toxicity. Nanotechnology-based drug delivery systems are a promising approach to fulfill the need for new delivery systems offering several advantages, such as high drug binding capacity due to their large surface area, improved solubility and bioavailability of hydrophobic drugs, extended drug half-life, improved therapeutic index, reduced immunogenicity, and the possibility for controlled release (S. S. Suri, et al., J. Occupational Med. and Toxicol., vol. 2, pp. 1-6, 2007, R. A. Petros, et al., Nature Reviews Drug Discovery, vol. 9, pp. 615-627, 2010, E. Brewer, et al., J. Nanomaterials, vol. 2011, Article ID 408675, pp. 1-10, 2011). Nanoparticles can also be synthesized with control over average size, size distribution and particle shape, all key factors related to cellular uptake mechanisms and improved penetration across biological barriers. Additionally, some nanoparticles offer the possibility for combined use as therapeutic and diagnostic/imaging tools. A new term, theranostics, has been recently proposed to describe these types of nanoparticles (D. Sun, Molecular Medicine, vol. 7, no. 6, pp. 1879, 2010). The successful development of nanoparticle based delivery systems is exemplified by the use of nanomaterials for anticancer drug formulations (M. Ferrari, Nature Reviews, vol. 5, pp. 161-171, 2005, M. E. Davis, et al., Nature Reviews Drug Discovery, vol. 7, pp. 771-782, 2008).
A primary challenge to realizing the full promise of nanoparticle based drug delivery is the lack of optimal strategies to achieve selective and efficient cellular targeting. The mechanism of NP uptake is dependent on particle size and shape (D. E. Owens III, et al., Int. J. Pharmacy, vol. 307, pp. 93-102, 2006, J. A. Champion, et al., J. Controlled Release, vol. 121, pp. 3-9, 2007, F. Alexis, et al., Molecular Pharmaceutics, vol. 5, pp. 505-515, 2007), and several competing uptake mechanisms result in undesired processes including off-target accumulation in other organs tissues and cells, rapid clearance from in vivo circulation (especially nanoparticles less than 5 nm) (S. V. Vinogradov, et al., Advanced Drug Delivery Reviews, vol. 54, pp. 135-147, 2002, H. S. Choi, et al., Nature Biotechnology, vol. 25, pp. 1165-1170, 2007), opsonization and macrophage clearance (D. E. Owens III, et al., Int. J. Pharmacy, vol. 307, pp. 93-102, 2006, J. A. Champion, et al., J. Controlled Release, vol. 121, pp. 3-9, 2007, F. Alexis, et al., Molecular Pharmaceutics, vol. 5, pp. 505-515, 2007, S. V. Vinogradov, et al., Advanced Drug Delivery Reviews, vol. 54, pp. 135-147, 2002, H. S. Choi, et al., Nature Biotechnology, vol. 25, pp. 1165-1170, 2007, M. D. Howard, et al., J. Biomedical Nanotechnology, vol. 4, pp. 133-148, 2008), and complement activation by proteins that results in hypersensitivity reactions (I. Hamad, et al., Molecular Immunology, vol. 45, pp. 3797-3803, 2008). Nanoparticles can be somewhat targeted by attaching ligands with specificity to receptors that are overexpressed in certain cells (i.e., folate and transferrin receptors in cancer cells (Wang, et al., ACSNano, vol. 3, pp. 3165-3174, 2009, P. S. Low, et al., Accounts of Chemical Research, vol. 41, pp. 120-129, 2008, C. H. J. Choi, et al., Proceedings of the National Academy of Sciences USA, vol. 107, pp. 1235-1240, 2010, M. B. Dowling, et al., Bioconjugate Chemistry, vol. 21, pp. 1968-1977, 2010, L. Han, et al., Molecular Pharmaceutics, vol. 7, no. 6, pp. 2156-2165, 2010), or targeting cell populations with high selectivity by grafting specific targeting moieties to cell surface receptors known to be expressed only on target cells (i.e. antibodies to target prostate-specific membrane antigen (PSMA) (A. K. Patri, et al., Bioconjugate Chemistry, vol. 15, pp. 1174-1181, 2004) or galactose to target asialoglycoprotein receptors on hepatocyte cells (C. Plank, et al., Bioconjugate Chemistry, vol. 3, pp. 533-539, 1992). Some interfering processes can be reduced by coating the nanoparticles with a hydrophilic polymer (i.e. PEG polymer brush or Stealth nanoparticles). PEG is a non-immunogenic, non-toxic and protein-binding resistant polymer. PEG coating of nanoparticles prevents opsonization by shielding surface charges, reducing macrophage clearance, increasing steric repulsion of blood components, and increasing hydrophilicity and in vivo circulation of nanoparticles (M. D. Howard, et al., J. Biomedical Nanotechnology, vol. 4, pp. 133-148, 2008, K. G. Neoh, et al., Polymer Chemistry, vol. 2, pp. 747-759, 2011). Given the recent focus on nanoparticle-based delivery systems, for example, in drug delivery methodologies, there exists a need for improved systems capable of enhanced delivery, in particular, in therapeutic settings.